Significance of hyperphosphatasemia in alcoholics with liver disease: An analysis of fifty-eight cases, with histologic diagnoses

Abstract

Alcoholic cirrhosis is associated with normal serum alkaline phosphatase levels, but significant hyperphosphatasemia may accompany biliary tract obstruction, fatty metamorphosis of the liver, florid cirrhosis, neoplastic or granulomatous infiltrations of the liver, hepatic abscesses and drug hepatoxicity. To evaluate the frequency, as well as the clinical and laboratory features of the various hepatobiliary disorders that increases in alkaline phosphatase in alcoholics, fifty-eight consecutive patients with alkaline phosphatase levels of 12 S.J.R. units or more were studied. In each patient, a tissue diagnosis was made by liver biopsy, surgery or autopsy. Five clinicopathologic groups were distinguished. Thirty-two patients were found to have florid cirrhosis. Their clinical picture varied from that of acute toxicity to one of apparent good health. The serum alkaline phosphatase levels ranged from 12 to 20 S.J.R. units. The scrum cholesterol level was normal or low, thus distinguishing these cases from the fatty liver syndrome in which these levels are elevated. In many cases the alkaline phosphatase level remained elevated even after the jaundice had cleared. Histologically, florid cirrhosis shows an active inflammatory process with intense bile duct proliferation. There is evidence that the ductules help form liver parenchyma. Since the alkaline phosphatase concentration in the ductule cells is high, it is postulated that these elements account for the increased serum levels of this enzyme. Eleven patients had intrahepatic cholestasis from fatty metamorphosis of the liver. The laboratory findings were similar to those seen in extrahepatic obstruction, with hyperbilirubinemia, hypercholestremia and an elevated serum alkaline phosphatase. Liver biopsy shows the liver cells to be markedly distended with fat, and the presence of bile plugs in the ductules. Adequate nutrition and abstinence from alcohol produces a prompt improvement and distinguishes this condition from extrahepatic obstruction. Zieve's syndrome with hyperlipemia and hemolytic anemia is a variant. The mechanism of cholestasis and hyperphosphatasemia may result from structural and functional changes in the bile ductules and microvilli. Three patients had extrahepatic obstruction of the biliary tract. Initially, two of these were believed to have intrahepatic cholestasis from fatty metamorphosis of the liver because of the liver biopsy findings. Ultimately, pancreatic carcinoma was discovered. Lack of improvement in the obstructive pattern despite adequate nutrition serves to exclude the fatty liver syndrome. The third patient was thought to have silent pancreatitis and possibly superimposed chlorpromazine hepatoxicity. Despite the reportedly increased incidence of cholelithiasis in cirrhotic subjects, gallstones appear to be an uncommon cause of jaundice. Ten patients had primary carcinoma of the liver. There was nothing to differentiate this group from the others. The alkaline phosphatase levels ranged from 12 to 66 S.J.R. units. Three had minimal jaundice. Four patients, who had SGOT levels over 500 units, died after a brief hospital course. Two alcoholics had granulomatous infiltrations of the liver causing hyperphosphatasemia. This was believed to be due to tuberculosis in both. Few clinical and laboratory features were characteristic for a group. Hepatoma was found only in elderly patients, while the fatty liver syndrome occurred in the young alcoholic. Fever can result from active liver disease or concurrent infection. With persistent spiking temperatures, cholangitis, liver abscesses and granulomatous diseases must be excluded. Ascites was a common finding in all groups and usually had the characteristics of a transudate, but three patients with hepatoma had an exudate. Ascitic fluid from six patients with hepatoma was examined for tumor cells and found to be negative. Massive firm hepatomegaly suggests neoplasm. Increased serum alkaline phosphatase activity and bromsulfalein retention, without a corresponding increase in serum bilirubin, may occur with infiltrative disease, abscess, neoplasm, florid cirrhosis and some hepatotoxic drugs. In the presence of an elevated serum alkaline phosphatase level the concurrent increase in serum bilirubin and cholesterol indicates intraor extrahepatic obstruction. An increase in serum bilirubin in the absence of an increase in serum cholesterol suggests florid cirrhosis or infiltrative disease. Nonvisualization of the gallbladder on cholecystograms is common in the presence of impaired hepatic function. Liver biopsy is of indisputable value in these cases, but the histologic findings must be interpreted in the light of clinical and laboratory findings. While the cirrhotic process itself may produce substantial increases in serum alkaline phosphatase activity, to attribute all phosphatase elevations to “active cirrhosis” may lead to serious diagnostic errors. In this study 25 per cent of the patients had hepatobiliary disease other than alcoholic liver disease. Careful consideration of the clinical and laboratory findings is imperative in each case.